Phase I study of ZD9331 on short daily intravenous bolus infusion for 5 days every 3 weeks with fixed dosing recommendations

Purpose: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatabl e thymidylate synthase inhibitor using a short daily infusion for 5 consecu tive days every 21 days. Patients and Methods: patients with refractory cancer or cancer for which n o standard therapy wets available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at t imed intervals in the first cycle for pharmacokinetic analysis. Results: Seventy-four patients were enrolled a, 12 dose levels from a start ing dose of 0.4 mg/m(2)/d to 16 mg/m(2)/d and 25 mg/d fixed dosing, of whic h 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m2/d. Myelosuppression was dose-limiting, consisting of thrombocytopeni a associated with neutropenic fever. Body-surface area did not correlate wi th drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events, Dose-limiting non-hematologic toxicity consisted of grade 3 erythematous maculopapular ra sh observed in one patient at 12 mg/m(2)/d and one patient at 25 mg/d. Phar macokinetic analysis showed nonlinearity, with clearance increasing with do se. The mean clearance and terminal half-life of the drug were 6.6 +/- 2.0 mL/min and 71.3 +/- 27.0 hours, respectively. Area-under-the concentration- time curve was a better predictor of toxicity than dose, using multiple lin ear regression analyses. Minor response (40% shrinkage of tumor) was observ ed in one patient with colorectal cancer treated at 12 mg/m(2)/d. Conclusion: The recommended dose for ZD9331 on this schedule is 25 mg/d. Ne utropenia, thrombocytopenia, and rash were dose-limiting, and efficacy stud ies in colorectal cancer are indicated. J Clin Oncol 19:1476-1484. (C) 2001 by American Society of Clinical Oncology.